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Discussion Section 13
Outbreak - an Epidemic of Thyrotoxicosis!
PART I
On the afternoon of June 16, 1985, an endocrinologist at the University of South Dakota, Sioux Falls, was examining a patient with recent-onset thyrotoxicosis (manifestations of excess thyroid hormone) when the patient mentioned that there were four other people in his small town with the same problem. The patient was the postmaster of Valley Springs, South Dakota (population 801). Just a few days earlier, the endocrinologist had read an abstract of a CDC investigation describing an epidemic of painless thyroiditis in York County, Nebraska, in early 1984. Although the cause was never determined, the most likely etiology was believed to be viral infection. By speaking with other local physicians, the endocrinologist identified seven other patients with possible thyrotoxicosis. Six of the patients lived in Valley Springs, and two lived in southwest Minnesota. All exhibited classic symptoms of thyrotoxicosis (anxiety, shortness of breath, palpitations, rapid heartbeat, weight loss), and all had markedly elevated thyroxine (T4) levels. All but one had abnormally low radioiodine thyroid uptakes. The endocrinologist called CDC and provided the EIS Officer with the information summarized in the line listing below. Question 1: Place yourself in the role of the EIS Officer. Based on the information provided above, can you say that an epidemic exists?
Question 2: What additional information might you try to collect on the phone call?
Additional discussions involved the EIS Officer, the South Dakota State Epidemiologist, the Director of the
South Dakota Department of Health Communicable Disease Program, and CDC staff. The South Dakota State Epidemiologist invited CDC to send a team to investigate the cluster in Valley Springs. Accordingly, the EIS Officer and a medical student departed from Atlanta for Sioux Falls, South Dakota, on June 23 to assist the state health department in an investigation. On the airplane, the Officer and medical student reviewed the differential diagnosis for thyrotoxicosis, as summarized in Table 2.
The
endocrinologist met the CDC investigators at the airport and gave them additional information about the
area. Valley Springs, S.D., is located about 15 miles east of Sioux Falls on Interstate 90. Luverne, Minn. (population 4,568), lies 10 miles to the east of Valley Springs. The economy of the entire area is agricultural and is based on the production of beef cattle. There are no physicians in Valley Springs. Luverne has one medical clinic and a community hospital. Specialty referrals for the entire area are generally made to Sioux Falls. At this point, the investigative team included the endocrinologist, staff from the South Dakota Health Department, the EIS Officer, and the medical student. Question 3: The state health officials want to proceed by conducting additional case finding, to determine the extent of the problem. Your supervisor wants you to conduct a quick case-control study to try and identify possible etiologies. What do you do? The investigators decided to start the investigation by interviewing the eight known case-patients in order to verify the disease process and to look for obvious etiologic clues. They took blood specimens from the case patients as well as from their family members.
Question 4: Was it appropriate to obtain blood specimens from case-patients and family members at
this point in this investigation? Why or why not?
The eight interviews produced no valuable etiologic clues. The case-patients were geographically clustered but seemed to have no identifiable common exposures. Blood specimens from case-patients and their family members underwent a variety of tests, including tests for virus-specific antibodies, T4, free T4, T3 resin uptake, and T3. While waiting for the blood test results, the team decided that the next step should be to increase case ascertainment. Question 5: What case-finding method(s) might you use?
Since radioactive-iodine-uptake scans were performed in only two facilities in the entire area, two hospitals in Sioux Falls, the team decided to begin case ascertainment by reviewing the results of all uptakes done there in the past year. They identified 33 patients with abnormally low uptakes. These patients were clustered around Luverne, Minnesota.
Question 6: How might you proceed?
PART II
Following discussions with the Minnesota State Epidemiologist, the Minnesota Department of Health joined the investigation. The investigators visited the only source of health care in Luverne, a clinic. The medical director of the clinic stated that he had seen an unusual number of elevated T4's lately, but said that he had ascribed the phenomenon to laboratory error. Team members reviewed the charts of all clinic patients with elevated T4's in the past year. They interviewed and obtained blood from all these patients and their families.
Laboratory results from the blood taken from the first 15 case-patients were now available. As expected, all had elevated free T4's. The team was startled to find, however, that 75% of asymptomatic family members of case-patients also had elevated T4's. The total number of case-patients with unexplained thyrotoxicosis was now 28. About five to eight new cases per week were being recognized at the Luverne
clinic. Patients' symptoms are shown in Table 3.
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The investigators agreed to widen case finding to define the extent of the outbreak. They decided to review patients' records from the medical clinics in five communities in southwestern Minnesota around Luverne, in southeastern South Dakota, and in northwestern Iowa for the previous 18 months. The team also planned to contact by telephone all physicians in eight counties in southwestern Minnesota and question them about the occurrence of thyrotoxicosis among their patients in the past 6 months. In addition, the investigators decided to send letters to all physicians in South Dakota and southwestern Minnesota describing the outbreak and requesting them to report suspected cases to their state health departments. In order to do this, team members decided that they needed a more formal case definition.
Question 7: Write the case definition that you would now use during widened case surveillance. How might this definition differ from the case definition you might use in a case-control study of the same illness?
PART III
A case was defined as an illness characterized by the presence of one or more values for T4, free T4, or T3 that were at least 25% higher than the upper limit of normal in the laboratory in which the test was performed, and included two or more of the following symptoms: sleeplessness, nervousness, headache, increased heart rate or palpitations, shortness of breath, fatigue, excessive sweating, tremor, diarrhea, heat intolerance, or weight loss. Patients were excluded if they had Graves' disease or if they had received thyroid hormone replacement therapy during the 2 months before diagnosis.
Question 8: What are the advantages and disadvantages of this case definition?
Widened surveillance produced additional cases (total N = 121). An age-sex breakdown of cases, an
epidemic curve, and an incidence map are shown in Table 4.
Sitting in a small country-western bar in Sioux Falls late at night in early September, the team members discussed their current hypotheses for the etiology of the outbreak on the basis of all the data accumulated so far. One member took a beer-dampened cocktail napkin and scratched out the major descriptive findings (time, place, person) that he knew about the cases so far. Question 9: What would you write on the cocktail napkin?
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Two nationally recognized thyroid experts were called in to provide consultation to the investigative team. After interviewing and examining several case-patients, they were perplexed by the outbreak but felt that the etiology was probably viral. Several team members favored iodine-induced hyperthyroidism as the most likely etiology; they felt that an accident might have occurred during the routine addition of iodine to flour. (An epidemic of thyrotoxicosis that occurred in Tasmania in the late 1960s was attributed
to the addition of potassium iodate to commercially baked bread as a prophylactic measure against goiter.) They decided to conduct an etiologic study as the next logical step.
Question 10: Exactly what type of study would you propose? Why?
PART IV
The investigators decided to carry out a case-control study. Case-patients were selected for the study if their illnesses fulfilled the case definition and if they had experienced the onset of symptoms in the previous six months. In households with more than one patient, only the family member with the earliest
onset of symptoms was included in the study. The first 44 patients who met these criteria were enrolled.
Question 11: Whom might you select as controls?
Question 12: What exposures would you ask about in the study?
PART V
Control subjects for the case-control study were randomly selected from local telephone directories and were matched to case-patients according to the following criteria: the same sex and telephone exchange, and age within 10 years of the corresponding patient if the patient was 30 years of age or older, and within 5 years if the patient was under 30 years of age. Just as the case-control study was getting under way, a new case-patient was diagnosed in Sioux Falls and was interviewed by some members of the investigative team. The woman, age 25, clearly had painless thyroiditis and hyperthyroidism. She lived in Sioux Falls but frequently visited a grocery store in Valley Springs, S.D., which her father owned. She sometimes purchased groceries there. Team members went to the store and interviewed the proprietor. All goods in the store were obtained from national distribution systems except two – chicken eggs and beef trimmings. The beef trimmings were obtained from a plant near Luverne. Some team members began to suspect that ingestion of beef may have been the source of the outbreak. They hypothesized that iodine contaminated the beef trimmings during processing, where it may have been used as a disinfectant. Then, during the case-control study, one investigator visited a family of four people where all members of the family except one had illness fulfilling the case definition. The one unaffected member was a young boy who was a vegetarian. The family obtained its meat from the Luverne beef plant. The results of the case-control study became available. The study showed that two factors were associated with illness – consumption of commercially processed chicken (odds ratio
2.3, p=0.03) and consumption of ground beef prepared by the Luverne plant (odds ratio 1.9, p=0.05). However, during the study, case patients were not asked about the source of their beef in a uniform way;
some team members suspected information bias.
The investigators decided to conduct a second case-control study to rule out any effect of information bias on the first case-control study and to obtain more information on specific exposures such as type of beef (hamburger, steak, roast) usually consumed and source of beef. The chicken was not implicated in the second study. Some of the results of the second case-control study are shown in Table 5.
Question 13: Interpret these results. How would you interpret the odds ratio of 0.08 for eating hamburger from privately slaughtered beef?
Question 14: What elements of causality, if any, were missing from the hamburger-thyrotoxicosis association at this point?
Question 15: What would be your recommendation regarding the beef plant now?
PART VI - CONCLUSION
Investigators went to the Luverne plant. The following is excerpted from a report of the plant investigation: "Two work shifts per day operated at Plant A, and approximately 800 animals were slaughtered and dressed during each shift. Before April 1983, thyroid glands were selectively removed and sold for use in the manufacture of thyroid extract. After that time, 'gullet trimming' was employed to harvest
muscle from the bovine larynx. In this procedure, the larynx was placed vertically on a peg 1 meter above the floor. The sternothyroid and sternohyoid muscles were removed from the larynx with a downward slicing motion... This motion allowed portions of both lobes of the thyroid gland to be inadvertently included in the muscle trimming... Although the process of gullet trimming was performed by a limited number of employees, the presence of thyroid tissue in the neck trimmings could not be attributed to any one employee.
"...Among the 22 boxes of beef trimmings produced before the recall that were examined, thyroid tissue was found in all
....
No thyroid tissue was found in four boxes produced after gullet trimming was discontinued. "When samples of the implicated beef were fed to volunteers, significant elevations of T4 and T3 occurred. "On August 29, 1985, because of this investigation, the USDA issued a nationwide advisory that temporarily prohibited gullet trimming in all USDA-inspected plants that slaughter beef
and pork." That prohibition was later made permanent.
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Screening
Use the following background information to answer questions 1 – 8:
A screening test for diabetes is used on 10,000 persons. The cut-off level employed was 180mg of blood
glucose per 100 ml or above as positive for diabetes. The prevalence of diabetes in this population is 5%. Among the sample of 10,000 individuals, a total of 150 people test positive for the disease, of which
25 do not have the disease. 1.
Set up the necessary 2x2 table and compute the (A) sensitivity and (B) specificity of the screening test. 2.
What do these values mean?